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The Perinatal Asphyxiated Lamb Model: A Model for Newborn Resuscitation

Birth asphyxia accounts for nearly one million deaths worldwide each year, and is one of the primary causes of early neonatal morbidity and mortality. ...

University at Buffalo

The optimal Fi(O2) during neonatal resuscitation is a subject of controversy. The effect of exposure to high levels of inspired oxygen on pulmonary arterial (PA) contractility is not known. We studied differences in PA vasoreactivity in term lambs initially ventilated with 21% or 100% oxygen, followed by continued ventilation using oxygen as needed for 24 h, or ventilated with 100% oxygen for 24 h and room air breathing 1-d-old lambs. Term lambs were delivered by cesarean section, intubated, and ventilated with 21% (21%Res) or 100% oxygen (100%Res) for the first 30 min of life. Subsequently, the ventilator Fi(O2) was adjusted to maintain a Pa(O2) between 45 and 65 mm Hg for 24 h. Five lambs were ventilated continuously with 100% oxygen (100%24h). Six spontaneously breathing newborn lambs (RA Spont) were studied for comparison. Lambs were killed at 24 h of life and PA rings were isolated and contracted with norepinephrine (NE) and KCl and some were relaxed with A23187 and SNAP in tissue baths. NE and KCl induced contractions were highest in PA isolated from 100%24h lambs, and were significantly higher in 100%Res lambs than PA from 21%Res lambs. Contraction responses in PA from RA Spont lambs were similar to 21%Res lambs. Relaxations to A23187 and SNAP were similar among all ventilated groups. PA contractility to NE and KCl is increased following both brief (30 min) and prolonged (24 h) exposure to 100% oxygen during mechanical ventilation. In contrast, normoxic resuscitation and ventilation do not increase PA contractility.

Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen resuscitation.

Stem cells have significant potential for development of cell-based therapeutics for cardiovascular tissue regeneration.

Functional tissue-engineered blood vessels from bone marrow progenitor cells.

An increase in oxygen tension is an important factor in decreasing pulmonary vascular resistance (PVR) at birth. Birth asphyxia results in acidosis and increased PVR. We determined the effect of resuscitation with 21 vs. 100% O(2) on pulmonary hemodynamics, pulmonary arterial (PA) reactivity, and oxidant stress in a lamb model of in utero asphyxia. Term fetal lambs were acutely asphyxiated by intrauterine umbilical cord occlusion for 10 min resulting in acidosis (pH 6.96 ± 0.05 and Pco(2) 103 ± 5 Torr), bradycardia, systemic hypotension, and increased PVR. Lambs were treated with 30 min of resuscitation with 21% or 100% O(2) (n = 6 each). Pa(O(2)) was significantly elevated with 100% O(2) resuscitation compared with 21% O(2) (430 ± 38 vs. 64 ± 8 Torr), but changes in pH and Pa(CO(2)) were similar. The 100% O(2) induced greater increase in pulmonary blood flow and decrease in PVR at 1 min of life, but subsequent values were similar to 21% O(2) group between 2 and 30 min of life. Oxygen uptake from the lung and systemic oxygen extraction was similar between the two groups. Pulmonary arteries showed increased staining for superoxide anions and increased contractility to norepinephrine following resuscitation with 100% O(2). The increased PA contractility induced by 100% O(2) was reversed by scavenging superoxide anions with superoxide dismutase and catalase. We conclude that resuscitation of asphyxiated lambs with 100% O(2) increases Pa(O(2)) but does not improve lung oxygen uptake, decrease PVR at 30 min, or increase systemic oxygen extraction ratios. Furthermore, 100% O(2) also induces oxidative stress and increases PA contractility. These findings support the new neonatal resuscitation guidelines recommending 21% O(2) for initial resuscitation of asphyxiated neonates.

Pulmonary hemodynamics and vascular reactivity in asphyxiated term lambs resuscitated with 21 and 100% oxygen.

The mechanisms contributing to hypoxia in lung contusion (LC) remain unclear and not temporally associated with the peak onset of acute inflammation. We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. In addition, the role of antioxidants in reversing this process was examined. PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a nitric oxide synthase (NOS) inhibitor, L-nitro arginine (10(-3) M), or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT), or both (L-nitro arginine + SOD/CAT). Rings were constricted with norepinephrine and relaxed with an NOS agonist (A23187) or NO donor (SNAP [S-nitrosyl amino penicillamine]). Immunochemical and mass spectrometric quantification for nitrotyrosine was performed. Rats were hypoxemic at 4 h after contusion compared with controls, but recovered by 24 h (PaO(2)/FIO(2) ratio: baseline, 443 ± 28; 4 h, 288 ± 46; and 24 h, 417 ± 23). Pulmonary arterial constriction to NOS inhibition and relaxation to A23187 were impaired 4 h after LC. Pulmonary arterial relaxation to SNAP was decreased at 4 and 24 h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA were upregulated, and soluble guanylyl cyclase mRNA was downregulated 24 h after LC. Immunohistochemistry and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4 h following LC consistent with superoxide generation and formation of peroxynitrite. Collectively, these data suggest that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC.

Role of pulmonary artery reactivity and nitric oxide in injury and inflammation following lung contusion.

Current neonatal resuscitation guidelines recommend tracheal suctioning of nonvigorous neonates born through meconium-stained amniotic fluid.

Tracheal suctioning improves gas exchange but not hemodynamics in asphyxiated lambs with meconium aspiration.

The oxygenation index (OI = mean airway pressure, MAP × FiO2 × 100 : PaO2) is used to assess the severity of hypoxic respiratory failure (HRF) and persistent pulmonary hypertension of the newborn (PPHN). An indwelling arterial line or arterial punctures are necessary to obtain PaO2 for the calculation of OI. Oxygenation can be continuously and noninvasively assessed using pulse oximetry. The use of the oxygen saturation index (OSI = MAP × FiO2 × 100 : SpO2) can be an alternate method of assessing the severity of HRF.

Oxygen saturation index and severity of hypoxic respiratory failure.

Intestinal circulation and mesenteric arterial (MA) reactivity may play a role in preparing the fetus for enteral nutrition. We hypothesized that MA vasoreactivity changes with gestation and vasodilator pathways predominate in the postnatal period.

Fetal and postnatal ovine mesenteric vascular reactivity.

The Neonatal Resuscitation Program (NRP) recommends upper and lower limits of preductal saturations (SpO2) extrapolated from studies in infants resuscitated in room air. These limits have not been validated in asphyxia and lung disease.

Neonatal resuscitation adhering to oxygen saturation guidelines in asphyxiated lambs with meconium aspiration.

The Neonatal Resuscitation Program (NRP) recommends close monitoring of oxygenation during the resuscitation of newborns using a pulse oximeter. However, there are no guidelines for monitoring carbon dioxide (CO2) to assess ventilation. Considering that cerebral blood flow (CBF) correlates directly with PaCO2, continuous capnography monitoring of end-tidal CO2 (ETCO2) may limit fluctuations in PaCO2 and, therefore, CBF during resuscitation of asphyxiated infants.

Continuous End-Tidal Carbon Dioxide Monitoring during Resuscitation of Asphyxiated Term Lambs.

Supplemental O to treat bronchopulmonary dysplasia (BPD) in premature infants, is a major risk factor producing alteration in lung function, airway reactivity, and predisposition to respiratory infections. This study explores inflammatory and airway responses following neonatal hyperoxia in adult mice.

Neonatal hyperoxia increases airway reactivity and inflammation in adult mice.

In neonates requiring chest compression (CC) during resuscitation, neonatal resuscitation program (NRP) recommends against relying on a single feedback device such as end-tidal carbon dioxide (ETCO) or saturations (SpO) to determine return of spontaneous circulation (ROSC) until more evidence becomes available.

Continuous capnography monitoring during resuscitation in a transitional large mammalian model of asphyxial cardiac arrest.

The Neonatal Resuscitation Program recommends initial resuscitation of preterm infants with low oxygen (O) followed by titration to target preductal saturations (SpO). We studied the effect of resuscitation with titrated O on gas exchange, pulmonary, and systemic hemodynamics.

Effect of various inspired oxygen concentrations on pulmonary and systemic hemodynamics and oxygenation during resuscitation in a transitioning preterm model.

Article	Year
Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen resuscitation. Pediatric research\| PubMed ID: 16326983	2006
Functional tissue-engineered blood vessels from bone marrow progenitor cells. Cardiovascular research\| PubMed ID: 17512920	2007
Pulmonary hemodynamics and vascular reactivity in asphyxiated term lambs resuscitated with 21 and 100% oxygen. Journal of applied physiology (Bethesda, Md. : 1985)\| PubMed ID: 21799125	2011
Role of pulmonary artery reactivity and nitric oxide in injury and inflammation following lung contusion. Shock (Augusta, Ga.)\| PubMed ID: 23364426	2013
Tracheal suctioning improves gas exchange but not hemodynamics in asphyxiated lambs with meconium aspiration. Pediatric research\| PubMed ID: 25406897	2015
Oxygen saturation index and severity of hypoxic respiratory failure. Neonatology\| PubMed ID: 25592054	2015
Fetal and postnatal ovine mesenteric vascular reactivity. Pediatric research\| PubMed ID: 26672733	2016
Neonatal resuscitation adhering to oxygen saturation guidelines in asphyxiated lambs with meconium aspiration. Pediatric research\| PubMed ID: 26672734	2016
Continuous End-Tidal Carbon Dioxide Monitoring during Resuscitation of Asphyxiated Term Lambs. Neonatology\| PubMed ID: 26866711	2016
Neonatal hyperoxia increases airway reactivity and inflammation in adult mice. Pediatric pulmonology\| PubMed ID: 27116319	2016
Continuous capnography monitoring during resuscitation in a transitional large mammalian model of asphyxial cardiac arrest. Pediatric research\| PubMed ID: 28157836	2017
Effect of various inspired oxygen concentrations on pulmonary and systemic hemodynamics and oxygenation during resuscitation in a transitioning preterm model. Pediatric research\| PubMed ID: 29967523	2018

Sylvia Gugino

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